Children’s researcher Zhe Han, Ph.D., has received a $2 million award from the National Institutes of Health (NIH) to study new approaches to treat kidney disease linked to inheriting Apolipoprotein L1 (APOL1) risk alleles. These risk alleles are particularly common among persons of recent African descent, and African Americans are disproportionately affected by the increased risk in kidney disease associated with these risk alleles.

Han, an associate professor in Children’s Center for Genetic Medicine Research, has established a leading research program that uses the fruit fly Drosophila as a model system to study how genetic mutations lead to disease.

“Drosophila is a very basic model, but studies in the fly have led to major breakthroughs in understanding fundamental biological processes that underlie health and disease in humans,” Han says. “Since coming to Children’s National five years ago, I have focused a significant part of my research studying particular fly cells called nephrocytes that carry out many of the important roles of human kidney glomeruli, units within the kidney where blood is cleaned. Working together with clinician colleagues here, we have demonstrated that these Drosophila cells can be used to very efficiently study different types of renal disease caused by genetic mutations.”

The APOL1 risk alleles are genetic variants, termed G1 and G2, found almost exclusively in people of African ancestry and can lead to a four-fold higher risk of end-stage kidney disease, the last of five stages of chronic kidney disease. Exactly how inheriting these risk alleles increases the risk of kidney disease remains an unanswered question and the focus of considerable research activity. Han’s laboratory has developed a Drosophila model of APOL1-linked renal disease by producing the G1 and G2 forms of APOL1 specifically in nephrocytes. This led to defects in fly renal cells that strikingly overlap with disease-associated changes in experimental model and human kidney cells expressing APOL1 risk alleles.

The new NIH award will fund large-scale screening and functional testing to identify new treatment targets and new drugs to treat kidney disease linked to APOL1. Using a genetic screening approach, Han’s lab will identify nephrocyte “modifier” genes that interact with APOL1 proteins and counter the toxic effects of risk-associated G1 and G2 variants.

The team also will identify nephrocyte genes that are turned on or off in the presence of APOL1 risk alleles, and confirm that such “downstream” APOL1-regulated genes are similarly affected in experimental model and human kidney cells. The potential of the newly identified “modifier” and “downstream” genes to serve as targets of novel therapeutic interventions will be experimentally tested in fly nephrocytes in vivo and in cultured mammalian kidney cells.

Finally, the Drosophila model will be used as a drug screening platform for in vivo evaluation of positive “hits” from a cell-based APOL1 drug screening study in order to identify compounds that are most effective with the fewest side effects.

“These types of studies can be most efficiently performed in Drosophila,” Han adds. “They take advantage of the speed and low cost of the fly model system and the amazing array of well-established, sophisticated genetic tools available for the fly. Using this model to elucidate human disease mechanisms and to identify new effective therapies has truly become my research passion.”

A Children’s researcher has received a $2 million grant from the National Institutes of Health (NIH) to study nephrotic syndrome in Drosophila, a basic model system that has revealed groundbreaking insights into human health. The award for Zhe Han, Ph.D., an associate professor in Children’s Center for Genetic Medicine Research, is believed to be the first ever NIH Research Project grant (R01) to investigate glomerular kidney disease using Drosophila. Nephrotic syndrome is mostly caused by damage of glomeruli, so it is equivalent to glomerular kidney disease.

“Children’s National leads the world in using Drosophila to model human kidney diseases,” Han says.

In order to qualify for the five-year funding renewal, Han’s lab needed to successfully accomplish the aims of its first five years of NIH funding. During the first phase of funding, Han established that nephrocytes in Drosophila serve the same functions as glomeruli in humans, and his lab created a series of fly models that are relevant for human glomerular disease.

“Some 85 percent of the genes known to be involved in nephrotic syndrome are conserved from the fly to humans. They play similar roles in the nephrocyte as they play in the podocytes in human kidneys,” he adds.

Pediatric nephrotic syndrome is a constellation of symptoms that indicate when children’s kidneys are damaged, especially the glomeruli, units within the kidney that filter blood. Babies as young as 1 year old can suffer proteinuria, which is characterized by too much protein being released from the blood into the urine.

“It’s a serious disease and can be triggered by environmental factors, taking certain prescription medicines or inflammation, among other factors. Right now, that type of nephrotic syndrome is mainly treated by steroids, and the steroid treatment works in many cases,” he says.

However, steroid-resistant nephrotic syndrome occurs primarily due to genetic mutations that affect the kidney’s filtration system: These filters are either broken or the protein reabsorption mechanism is disrupted.

“When genetics is to blame, we cannot turn to steroids. Right now there is no treatment. And many of these children are too young to be considered for a kidney transplant,” he adds. “We have to understand exactly which genetic mutation caused the disease in order to develop a targeted treatment.”

With the new funding, Han will examine a large array of genetic mutations that cause nephrotic syndrome. He’s focusing his efforts on genes involved in the cytoskeleton, a network of filaments and tubules in the cytoplasm of living cells that help them to maintain shape and carry out important functions.

“Right now, we don’t really understand the cytoskeleton of podocytes – highly specialized cells that wrap around the capillaries of the glomerulus – because podocytes are difficult to access. To change a gene requires time and considerable effort in other experimental models. However, changing genes in Drosophila is very easy, quick and inexpensive. We can examine hundreds of genes involving the cytoskeleton and see how changing those genes affect kidney cell function,” he says.

Han’s lab already found that Coenzyme Q10, one of the best-selling nutrient supplements to support heart health also could be beneficial for kidney health. For the cytoskeleton, he has a different targeted medicine in mind to determine whether Rho inhibitors also could be beneficial for kidney health for patients with certain genetic mutations affecting their podocyte cytoskeleton.

“One particular aim of our research is to use the same strategy as we employed for the Coq2 gene to generate a personalized fly model for patients with cytoskeleton gene mutations and test potential target drugs, such as Rho inhibitors.” Han added. “As far as I understand, this is where the future of medicine is headed.”

Myriad biological and societal factors can impact the occurrence and accelerate progression of chronic kidney disease for children of African descent – including preterm birth, exposure to toxins during gestation and lower socioeconomic status – and can complicate these children’s access to effective treatments.

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Myriad biological and societal factors can impact the occurrence and accelerate progression of chronic kidney disease (CKD) for children of African descent – including preterm birth, exposure to toxins during gestation and lower socioeconomic status – and can complicate these children’s access to effective treatments, according to an invited commentary published in the November 2018 edition of American Journal of Kidney Diseases.

Clinicians caring for “these vulnerable children should be mindful of these multiple competing and compounding issues as treatment options are being considered along the continuum from CKD to kidney failure to transplantation,” writes Marva Moxey-Mims, M.D., chief of the Division of Nephrology at Children’s National Health System.

The supplemental article was informed by lessons learned from The Chronic Kidney Disease in Children (CKiD) longitudinal study and conversations that occurred during the Frank M. Norfleet Forum for Advancement of Health, “African Americans and Kidney Disease in the 21st Century.”

African American children represent 23 percent of the overall population of kids with CKD in the CKiD study. While acquired kidney diseases can get their start during childhood when the diseases betray few symptoms, the full impact of illness may not be felt until adulthood. A number of factors can uniquely affect children of African descent, heightening risk for some kids who already are predisposed to suffering more severe symptoms. These include:

Preterm birth. African American children make up 36 percent of patients in CKiD with glomerular disease, which tends to have faster progression to end-stage renal disease. These diseases impair kidney function by weakening glomeruli, which impairs the kidneys’ ability to clean blood. Patients with a high-risk apolipoprotein L1 (APOL1) genotype already are at higher risk for focal segmental glomerulosclerosis (FSGS) and CKD. Researchers hypothesize that preterm birth may represent “a second hit that facilitates the development of glomerular damage resulting from the high-risk genotype.” According to the Centers for Disease Control and Prevention, 1 in 10 U.S. infants in 2016 was born preterm, e.g., prior to 37 weeks gestation.

APOL1 genotype. Compared with children who had a low-risk genotype and FSGS, children with a high-risk genotype had higher rates of uncontrolled hypertension, left ventricular hypertrophy, elevated C-reactive protein levels and obesity.

Human immunodeficiency viral (HIV) status. About 65 percent of U.S. children with HIV-1/AIDS are African American. In a recent nested case-control study of children infected with HIV in the womb, infants with high-risk APOL1 genotypes were 3.5 times more likely to develop CKD with viral infection serving as “a likely second hit.”

Access to kidney transplant. African American adults experience a faster transition to end-stage renal disease and are less likely to receive kidney transplants. African American children with CKD from nonglomerular diseases begin renal replacement therapy 1.6 years earlier than children of other races, after adjusting for socioeconomic status. Their wait for dialysis therapy was 37.5 percent shorter. However, these African American children waited 53.7 percent longer for transplants. Although donor blood types, genetic characteristics and other biological factors each play contributing roles, “these findings may reflect sociocultural and institutional differences not captured by socioeconomic status,” Dr. Moxey-Mims writes.

To alleviate future health care disparities, she suggests that additional research explore the impact of expanding services to pregnant women to lower their chances of giving birth prematurely; early childhood interventions to help boost children’s educational outcomes, future job prospects and income levels; expanded studies about the impact of environmental toxicities on prenatal and postnatal development; and heightened surveillance of preterm infants as they grow older to spot signs of kidney disease earlier to slow or prevent disease progression.

“Clinicians can now begin to take into account genetics, socioeconomic status and the impact of the built environment, rather than blaming people and assuming that their behavior alone brought on kidney disease,” Dr. Moxey-Mims adds. “Smoking, not eating properly and not exercising can certainly make people vulnerable to disease. However, there are so many factors that go into developing a disease that patients cannot control: You don’t control to whom you’re born, where you live or available resources where you live. These research projects will be useful to help us really get to the bottom of which factors we can impact and which things can’t we prevent but can strive to mitigate.”

The article covered in this post is part of a supplement that arose from the Frank M. Norfleet Forum for Advancement of Health: African Americans and Kidney Disease in the 21st Century, held March 24, 2017, in Memphis, Tennessee. The Forum and the publication of this supplement were funded by the Frank M. Norfleet Forum for Advancement of Health, the Community Foundation of Greater Memphis and the University of Tennessee Health Science Center.

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